The thesis research proposed entitled "Small Molecules that Prevent Transthyretin (TTR) Fibril Formation by Binding to and Stabilizing the Native Folded State of Transthyretin" is a novel approach for therapeutic intervention in amyloid disease. This proposal is made possible by preliminary results obtained by Greta Miroy and Vicky Lai in the Kelly Laboratory showing that the native ligand for TTR binds to and stabilizes TTR against fibril formation by preventing the conformational changes required for TTR amyloid formation. This approach for preventing TTR fibril formation should apply to the other fifteen amyloid diseases and be liable in vivo for the reasons outlined within. My thesis research will be centered around a structure-based drug design approach to be used in combination with a directed combinatorial chemistry approach to design high affinity ligands that prevent TTR fibril formation in vitro. In this proposal I have stressed the background, preliminary results and the conceptual approach to be used. At the present time I am not an expert at applying a structure-based/combinatorial approach to solve this problem-this is what l will learn. However, several experiments have been outlined which are well documented, but are subject to change based on further developments and results. While I have not stressed extension of these results to animal models such models do exist and plans are now being made with an established collaborator (Joel Buxbaum) to test the best compounds in those mice. These experiments should prove to be very important to probe the assumption that amyloid fibril formation results in amyloid disease, which has not been proven.